3. Cortical dysfunction in Machado–Jospeh disease

Abstract

Background and aims Machado Joseph Disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3) is an inherited neurodegenerative disorder characterized by cerebellar ataxia and variable expression of clinical features beyond the cerebellum, including amyotrophy and motor neurone disease. To gain further insights into motor cortex pathophysiology in MJD, the present study investigated whether threshold tracking transcranial magnetic stimulation could detect cortical dysfunction and whether this contributed to the development of clinical manifestations. Methods Clinical assessments were combined with threshold-tracking transcranial magnetic stimulation and peripheral nerve excitability techniques in 11 genetically characterized MJD patients and results compared to 40 age-matched healthy controls. The International Cooperative Ataxia Rating Scale (ICARS) was used to quantify the severity of ataxia in MJD patients. Results Clinical severity varied, ranging from presymptomatic in 2 patients to severe as reflected by the broad spectrum in ICARS score (range 0–59, median 27). Short-interval intracortical inhibition (SICI) was significantly reduced in presymptomatic (5.3 ± 0.5%) and symptomatic MJD patients (-1.3 ± 1.4%) compared to healthy controls (10.3 ± 0.7%, P 0.0001), evident prior to clinical onset of ataxia and related to worsening severity (R = −0.67, P 0.05). SICI reduction was accompanied by decreases in resting motor threshold and cortical silent period in pre-symptomatic patients and inversely related to severity of clinical ataxia. CMCT was also significantly prolonged in all MJD patients (symptomatic MJD 7.5 ± 0.4 ms; pre-symptomatic MJD 6.2 ± 0.5 ms controls 5.3 ± 0.2 ms, P 0.0005) and a feature of neurodegeneration related to clinical severity (R = 0.72, P = 0.01). Markers of peripheral motor neurodegeneration and excitability were not associated with cortical hyperexcitability or ataxia. Conclusion Simultaneous investigation of clinical status, central and peripheral nerve excitability has established that cortical dysfunction is evident in patients with MJD and precedes the development of cerebellar symptoms, ataxia and peripheral neurodegeneration. Taken together this indicates that cortical dysfunction may be an early feature that may herald widespread neurodegeneration in MJD.